Process for preparation of n-glycosides of 5, 6 dimethyl benzimidazoles



Patented Dec. 1 5, 1953 SIDES OLES OF 5,6 DIMETHYL BE NZ IMIDAZ- Frederick W. Holly, .Cranford, Clifford HJ Skunk, :Westfield, and Karl Folkers, Plairifield, N. J., .assignors to Merck-.85 00., Inc., Rahway, N. J.,

a corporationofNew Jersey No Drawing. Application Mayi3, 1950, Serial vN0. 159,878

Claims. (01. 260-I-:2I1.5)

This invention relates to the preparation of chemical compounds having growth-stimulating .or vitamin-like activity and, more particularly,to the preparation of N-glycosides of 5 ,6-dimethylbenzimidazole which:may be represented by the .followingiormula:

4 /NR CH 3 OH CH3 wherein R'is a glycosido radical having at least '4 carbon'atoms. These'compounds are-characterized by'a glycosidiclinkage of the-type:

O f I -rr as expressed by the generic name ofN-glycosides.

In-our pending application Serial No..124,236, filed October 28, 1949, now Patent No. 2,644,817,

'we have originally disclosed and claimed :these "N-glycosides of 5,6-dimethylbenzimidazole "and certain procedures for their preparation. The

"disclosed procedure involves reacting an aldosugar with '2 nitro 4,5 dimethylaniline to form The 5,6-dimethy1benzimidaz0le may in turn be prepared by condensing 4,5-diamino-1,2-dimethylbenzene with formic acid as described'by vBrinkand Folkers, J. Amer. Chem. Soc., '11, 2951 The acylated halosugars which are particularly desirable for this reaction are those having at least 4 carbon atoms and a halogen atom in the 1 position; these compounds may be prepared by various known methods such as, for example, by acylating an aldosugar and treating the resulting acylated product with'hydrogen chloride.

In carrying out the-process of the present invention 1 the silver saltof 5:6 -HimethylbenZiniid-a- 'zol'e is first suspended Y in an inert organic liquid. Suitable organic liquids include solvents such as "benzene, xylene, tolu=ene,-and the 5 like. An acylated halosugar is then added tothe suspension and the reaction mixture i's heated -under reflux for a-short'period of time. Aftercompletion'of the reaction the mixture is cooled'and filtered. The organic liquid is 'thenevaporated 'from'the reaction mixture-yieldingan 'acylated N-glycoside as a crude residue. The acylated N-glycosideis then deacylated, and the resulting product is treated with aqueous 'pi'cri'c acid 'to precipitate crystals of N-glycoside of 5ffi-dimethylbenz'i'midazole.

' The 'deacylation o'fthese compounds may be accomplished by heating theiacylated compound in an alcoholic solution in the presence of an alkali metal 'alc'oholate. We have "obtained ex- -cellen tiresults with the nse'of sodium methoxide.

Alternatively, the acylate'dncomp'ound is dea'cyl- -aitedby "heating with'an aqueous mineral-acid.

By use of the appropriate acyl'ated rhalosugar 'ou'r'p'rocess is applicable topynthesis ofzany one of "the 4 isomers derive-d irom any given carbohydrate; 1 it is applicable to the -synthe'si's'of thenand B- forms of the furanose and pyranose ring systems.

The-conversion ofthepicrates to the free bases may be accomplished by conventional methods "such as continuous chloroform extraction of an alkaline solution of the picrates which yields a "chloroform ex'tr-ac't containing the glycoside.

\carrying out the present invention, butitis tofbe understood that these examples aregiven by way of iIIustration andinot of limitation.

EXAMPLE 1 Preparation of 5.6-dimet'hylbenaimiddzdle silver salt b'en'zimi'dazole in 200 parts of warm 6 N ammonium hydroxide and 20 parts of ethanol was added a solution of 1.9 parts' ef silver -nitratein parts of water. The mixture was chilled and the precipitate was collected on a filter and washed with cold dilute aqueous ammonia; 2.5 parts of 5,fi-dimethylbenzimidazole silver salt was obtained as a white solid.

EXAMPLE 2 Preparation of Z-L-arabinopyranosido- 5,6-dimethylbenzimidazole One part of the silver salt of 5,6-dimethylbenzimidazole was suspended in parts of xylene containing 1.3 parts of 1-bromo-2,3,4-tria-cetyl-L- arabinose, and the mixture was refluxed for ten minutes. After cooling and filtering, the solvent was evaporated under reduced pressure giving 1 L triacetylarabinosido 5,6 dimethylbenzimidazole as an oil.

EXAMPLE 3 Deacetylation with sodium methoxide The triacetylarabinosido-5,6-dimethylbenzimidazole was dissolved in parts of absolute ethanol, and 0.19 part of sodium methoxide were added. After the solution was refluxed for one hour, it was evaporated under reduced pressure and the residue was partitioned between chloroform and water. After extraction of the aqueous layer with chloroform, it was neutralized with dilute hydrochloric acid and excess aqueous picric acid was added. The precipitate which separated was collected, washed with water, and dissolved in hot ethanol. Yellow prisms separated slowly as the solution cooled. Recrystallization from 15 parts of ethanol gave yellow platelets of 1-L-arabinopyranosido-5,6-dimethylbenzimidazole picrate. The compound was a pyranoside since 1.8 moles of periodate were consumed in a forty-seven hour period.

AnaL-Calcd. for CzoELnNaOn: C, 47.34; H. 4.17; N, 13.80. Found: C, 47.67; H, 3.92; N, 14.09.

EXAMPLE 4 Deacetylation with mineral acid The triacetylarabinosido 5,6 dimethylbenzimidazole was dissolved in 10 parts of ethanol; 20 parts of water and 3 parts of concentrated hydrochloric acid were added After the solution was refluxed for two hours, it was evaporated under reduced pressure to one-half volume and made alkaline with dilute sodium hydroxide.

The mixture was extracted with three portions of chloroform and then made slightly acid with dilute hydrochloric acid. The addition of aqueous picric acid gave a precipitate which was collected and dried under reduced pressure giving yellow crystals that were recrystallized from methanol yielding 1-L-arabiopyranosido-5,6-dimethylbenzimidazole picrate.

EXAMPLE 5 Preparation of 1-e-D-glucopyranosido-5,6 di methylbenzimidazole acid, and extracted again with chloroform. A clear solution was obtained, to which an aqueous solution of picric acid was added to isolate the glucoside conveniently as a picrate. The yellow crystalline product was recrystallized from ethanol-water to give 1-;3-D-glucopyranosido-5,6-dimethylbenzimidazole picrate.

Anal.--Calcd. for C21H23N5O122 N, 13.03, Combining weight, 308. Found: N, 13.16; Combining weight, 293.

EXAIWPLE 6 Preparation of 1-L-arabinofuranosido-5,6-

dimethylbenzimidazole L-arabinose was tritylated by the usual procedure and the oily 5-trityl-L-arabinose was acetylated in pyridine and acetic anhydride at 0 C. The oily 1,2,3-triacetyl-B-trityI-L-arabinose was hydrogenated in methanol over palladium- Darco (5% palladium), to yield triacetyl-L- arabinofuranose which was reacetylated in pyridine and acetic anhydride at 0 C. The resulting tetraacetyl-L-arabinofuranose was dissolved in ether saturated with hydrogen chloride and the solution was kept at 0 C. for twenty hours. The solvent was removed by evaporation in vacuo and the oily residue containing l-chlorotriacetyl- L-arabinofuranose was refluxed with 2 parts of 5,6-dimethylbenzimidazole silver salt in 50 parts of xylene for five hours. The mixture was illtered and the filtrate was concentrated in vacuo to an oil containing crystals of triphenylchloromethane. The mixture of oil and crystals was refluxed for 2 hours with 5% hydrochloric acid containing sufiicient ethanol to dissolve the products. The solids which separated were removed by filtration, the filtrate was concentrated in vacuo, the residue was dissolved in water and the solution was adjusted to pH 9 with sodium hydroxide and extracted three times with chloroform. After the aqueous layer was adjusted to pH 2 with hydrochloric acid, an aqueous solution of picric acid was added. The picrate obtained was recrystallized from water-methanol giving l-L-arabinofuranosido-5,6-dimethylbenzimidazole picrate.

Various changes and modifications in the foregoing procedure will occur to those versed in the art, and to the extent that such changes and modifications fall within the purview of the appended claims it will be understood that they constitute part of our invention.

We claim:

1. The process for preparing N-glycosides of 5,G-dimethylbenzimidazole having the formula:

r. a t CH:

on 0H3 wherein R is a glycosido radical having at least 4 carbon atoms, which comprises heating the sliver salt of 5,fi dimethylbenzimidazole with an acylated halosugar containing at least 4 carbon atoms in an inert organic solvent.

2. The process for preparing N-glycosides of 5,G-dimethylbenzimidazole having the formula:

N CH:

I on 01-13 wherein R is a glycosido radical having at least 4 carbon atoms, which comprises heating the silver salt of 5,fi-dimethylbenzimidazole with an acylated halosugar containing at least 4 carbon atoms in an inert organic solvent, and subjecting the resulting reaction product to hydrolysis to remove the acyl substituents.

3. The process for preparing l-L-arabinopyranosido-5,6-dimethylbenzimidazole which comprises heating the silver salt of 5,6-dimethylbenzimidazole with 1-bromo-2,3,4-triacetyl-L- arabinose in an inert organic solvent, and deacetylating the resulting product by hydrolysis.

4. The process for preparing l-fi-D-glucopyranosido-5,G-dimethylbenzimidazole which comprises heating the silver salt of 5,6-climethylzimidazole with acetobromoglucose in an inert organic solvent, and deacetylating the resulting product by hydrolysis.

5. The process for preparing 1-L-arabinofuranosido-5,6-dimethylbenzimidazole which comprises heating the silver salt of 5,6-dimethylbenzimidazole with 1-chloro-triacetyl-L-arabinofuranose in an inert solvent, and deacetylating the resulting product by hydrolysis.

FREDERICK W. HOLLY. CLIFFORD H. SHUNK. KARL FOLKERS.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,522,854 Brink et a1 Sept. 9, 1950 FOREIGN PATENTS Number Country Date 281,008 Germany Dec. 10, 1914 OTHER REFERENCES 

1. THE PROCESS FOR PREPARING N-GLYCOSIDES OF 5,6-DIMETHYLBENZIMIDAZOLE HAVING THE FORMULA: 